1. Field of the Invention
The present invention relates to the field of therapeutic treatment of human or animal cancer. The present invention relates in particular to a family of phosphorus containing carbohydrate analogues comprising a phosphinane ring, and prophylactic or therapeutic pharmaceutical compositions for use in human or veterinary medicine.
2. Description of Related Art
According to recent statistics, cancer is the second cause of death in France after cardiovascular diseases. The measures taken to fight against cancerous diseases do require multiplying the early diagnoses, but also improving the drug treatments. Discovering new original molecules, the specificity for tumoral cells of which as compared to healthy cells would be complete, would enable to develop new therapies.
Prior to choosing a therapy against cancer, some parameters have to be considered: the cancer type (sarcoma, melanoma . . . ), the affected organ, the cancer evolution stage, the whole prognostic factors and the patient own characteristics (age, global health status, psychism . . . ). From these data, a therapy may be selected, whether locally or globally. The most efficient treatments are local therapies that combine surgical and/or radiotherapeutic methods. They do treat less developed affections and heal most of localized cancers. General therapies, i.e. chemotherapy and/or hormonotherapy are typically palliative or auxiliary treatments. These treatments are implemented for localized and more developed cancers that may result in complicated metastases not yet clinically revealed. They make it possible to heal a limited number of generalized cancers but do improve the life expectancy of the patients (see Capdeville R., Buchdunger E., Zimmermann J., Matter A., Nature Rev. Drug Discov., 2002, 1, 493; Eisenberg B. L., Von Mehren M., Expert Opin Pharmacother., 2003, 6, 869; Gilman A., Philips F. S., Science, 1946, 103, 409; Gingras D, Beliveau R. Med. Sci., 1997. 13, 1428-35).
The limitation concerning the use of known antitumoral drugs results from their high toxicity, which causes many various side effects that might even lead to the patient death. “Chemical weapons” used for treating cancer are supposed to kill the tumoral cells while preserving the healthy cells. However the selectivity still remains highly relative as most of the drugs that are used in chemotherapy do present a non negligible haematological toxicity. Reducing the harmful side effects, especially those having serious consequences on the medical and psychic level, is as much important as attempting to improve the efficiency of a given drug. Taken all round, the whole range of drugs of the actual chemotherapist still comprises old highly cytotoxic drugs, as most of known antitumoral drugs are already more than about ten years old, and are very poorly targeted, at least on cellular level and do not offer any alternative to the resistance phenomena. Therefore there is a need for new antitumoral molecules, that can be used in chemotherapy, and that most preferably would only target the tumoral cells.
Sugars, which represent a family of biomolecules being omnipresent in the living world and comprising lots of different structures and functions, have many therapeutic applications: they aid fighting against obesity, diabetes, but also act as antivirus, antibiotic and antitumoral agents. Sugar analogue synthesis is interesting as these compounds may interfere with the various receptors or enzymes that do imply sugars, especially the energetic or biosynthetic mechanisms of some molecules, glycoconjugates, as well as the cell interadhesion mechanisms.
In the field of carbohydrate cyclic analogue preparation, two main axes have already been developed: The substitution of a carbon moiety for the hydroxyl group at the anomeric position (C-arylglycosides), and the substitution of another heteroatom for the intracyclic oxygen atom (phosphosugars, phosphasugars, iminosugars, thioglycosides).
C-aryl glycosides have demonstrated various biological activities and are largely used for treating diabetes, especially the type II diabetes, obesity or atherosclerosis.
The first family of cyclic phosphorus containing analogues of sugars that was synthesized was the phosphosugar family, by Wang and Whistler in 1968. These researchers described the preparation of a D-xylopyranose phosphinic analogue, i.e. 5-phospha-D-xylose (Whistler, R. L.; Wang, C. -C. Journal of Organic chemistry 1968, 33, 2495-2497 and 4455-4458).
There are two known phosphosugar families: the phosphonosugars, also known as phostones, and the phosphinosugars. The phosphinosugar family standing half-way between C-aryl-glycosides and phosphonosugars did not arouse much attention. The structures of the compounds that are representative of such large families are given in the scheme hereunder, wherein R represents an aryl or an alkyl group and R′ represents an aryl, alkyl, alkoxy or aryloxy group:

The two first phosphinosugars have been described in furanosic compound series in 2003 in Bisseret, P.; Boiteau, J. G.; Eustache, J. Tetrahedron Lett. 2003, 44, 2351-2354. Since then, two other compounds of this family have been prepared in pyranose compound series in Cristau, H. -J., Monbrun, J., Schleiss, J., Virieux, D., Pirat, J. -L., Tetrahedron Lett., 2005, 46, 3741-3744. However, nothing was mentioned concerning any particular biological activity for these phosphinosugars. The structures of known phosphinosugars are presented in the scheme hereafter:

Now the present inventors discovered that new sugar analogue, heterocyclic phosphonic compounds have a cytotoxic activity on tumoral cell mimetics, without any cytotoxicity against healthy cells. As used herein, healthy cells mean non-tumor cells.